The presence of chronic diseases in the differential (autoimmune and metabolic etiologies) reflects the fact that those conditions can have an asymptomatic course that can (rarely) initially present as acute on chronic liver failure. Acute liver failure is a systemic illness requiring supportive care in the hopes of hepatocyte regeneration. The only definitive treatment is liver transplantation.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

As stated by the American association for the Study of Liver Diseases (AASLD), the diagnosis of ALF is established in any patient who presents moderate to severe acute hepatitis with an elevated prothrombin time/INR (4-6 seconds or more/INR ≥1.5) and with evidence of altered sensorium.

Laboratory testing depends on whether the patient has acute liver failure and what is the suspected etiology of acute liver failure. Testing then becomes important in four different uses.

Does the patient have hepatic disease?

Biochemically, markers of hepatocellular damage will reflect the toxic/ischemic injury that can lead to acute liver failure. Not all cases of toxic/ischemic hepatic injury progress to acute liver failure, but they are the first step in its evolution. Of note, the literature does not clearly define what percentage of cases with toxic/ischemic injury progress to acute liver failure.

Typically, acute marked elevations of aminotransferases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >40x upper limit of normal (ULN) followed by a rapid decrease) signal the possibility of this type of injury. AST/ALT elevations greater than 75 times ULN indicate toxic/ischemic injury in 90% of cases.

There are other biochemical markers used to diagnose the presence of liver disease, such as albumin, bilirubin, alkaline phosphatase, gamma glutamyl transpeptidase and alpha-fetoprotein; however, these are usually not initially elevated in cases of acute liver failure.

Does this hepatic dysfunction qualify as acute liver failure?

Elevated prothrombin time/INR (4-6 seconds or more/INR>=1.5) in the appropriate clinical setting is the biochemical criteria.

What is the etiology of ALF (if identifiable)?

Acetaminophen Toxicity (39%; see chapter on acetaminophen poisoning)

Individuals that present with acute marked elevations of aminotransferases with no previous medical history should have an acetaminophen level checked. It is recommended that acetaminophen levels be checked in all patients that clinically present as a drug overdose due to the potential complications associated with acetaminophen toxicity. However, aminotransferase levels may not be elevated if the ingestion was relatively remote or if taken chronically.

Hepatic toxicity is based on a determination using the RUMACK nomogram that incorporates acetaminophen level relative to time of ingestion. This can only be used for acute ingestions. It is not designed for chronic intake or time release preparations. In addition, there is debate as to how effective the nomogram would be if alcohol was ingested with acetaminophen. As subsequently discussed, prognostic/transplant criteria are sorted by acetaminophen versus nonacetaminophen etiologies.

Drug Induced Hepatotoxicity (nonacetominophen)

A detailed drug history is imperative, as well as comprehensive drug screening, to determine if the etiology is drug related. The list of potential hepatic drugs is too numerous to mention here.

Viral Hepatitis (12%; see chapter on individual viral hepatitis)

Acute infectious hepatitis is responsible for about of 12% of cases of ALF. Hepatitis B (HBV) accounts for two-thirds, and hepatitis A (HAV) is associated with most of the remainder. Also reported are associations with hepatitis C (HCV), hepatitis delta (coinfection or superinfection), Epstein Barr virus, cytomegalovirus, herpes simplex, and varicella. Appropriate hepatitis serologies, such as anti-HAV IgM, HBSAg, anti-HBc IgM, and anti-HEV, are, therefore, indicated in cases where the etiology is uncertain.

Wilson's Disease (2-3%; see chapter on Wilson's Disease)

Ceruloplasmin level is decreased but may be normal in up to 15% of cases.

Copper (serum, urine) is elevated.

In addition, Wilson's disease typically has an associated acute hemolytic anemia with markedly elevated levels of serum bilirubin (>20 mg/dL) and decreased alkaline phosphatase. A bilirubin to alkaline phosphate ratio greater than 2.0 has been noted in cases of ALF. Renal function should be monitored as elevated serum copper levels can result in tubular damage.

Autoimmune Hepatitis (see chapter on Autoimmune Hepatitis)

Autoimmune markers (anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA)) can be present, as well as a polyclonal elevation in gamma globulin (primarily IgG). This can be a difficult diagnosis to make biochemically and may require a liver biopsy.

A type of ALF found near the end of pregnancy is known as HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets). Criteria (given but not consensed on) are listed as follows:

Microangiopathic hemolytic anemia

Platelet count less than or equal to 100, 000 cells/uL

Serum LDH greater than or equal to 600 IU/L or total bilirubin greater than or equal to 1.2 mg/dL

Serum AST greater than or equal to 70 IU/L

Hypoglycemia has also been reported in cases of HELLP syndrome.

Shock/Hypoperfusion

There are no biochemical markers, other than those related to toxic/ischemic injury, specific for shock/hypoperfusion related etiologies.

Vascular Disease

There are no biochemical markers, other than those related to toxic/ischemic injury, specific for vascular disease related etiologies.

What is the prognosis and potential for liver transplant?

Favorable outcome is based on degree of encephalopathy, age, prothrombin time, and etiology. Degree of encephalopathy, by itself, has not been used to determine the probability of spontaneous recovery or not.

With the given variables, the Kings College Hospital criteria were developed to determine prognosis for possibility of liver transplant:

Non-acetaminophen Induced

Prothrombin time greater than 100 seconds (irrespective of degree of encephalopathy)

Any three of the following five variables (irrespective of degree of encephalopathy):

Younger than 10 years of age or older than 40 years of age

Prothrombin time greater than 50 seconds

Serum bilirubin greater than 18 mg/dL

Cause; Drug toxicity, non-A, non-B hepatitis

Duration of jaundice before encephalopathy greater than 7 days

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Aminotransferases (AST and ALT)

Both enzymes are ubiquitous throughout the body, although ALT is more specific to the liver than AST. Both can be elevated in multiple conditions, such as hemolysis, myocardial infarction, and rhabdomyolysis. However, there are no conditions that will elevate AST and/or ALT to the degree seen with ischemic liver injury. Conversely, the assays for AST and ALT use pyridoxal phosphate (PLP; vitamin B6); therefore, in cases of malnourishment, it is possible to have a falsely-depressed level. However, no degree of vitamin B6 deficiency should be able to depress AST or ALT to mask the possibility of ischemic liver injury.

Prothrobin time/INR

Ammonia

Arterial specimens are better than venous. Specimens should be collected on ice and rapidly transported to the laboratory. Results are very susceptible to external contaminants, such as cigarette smoke and incorrect specimen tube. Ammonia levels will also be elevated in urea cycle related inborn errors of metabolism.

What Lab Results Are Absolutely Confirmatory?

The diagnostic criteria are the confirmatory tests.

Additional Tests of Importance

Acute liver failure is a critical systemic illness; therefore, all standard biochemical and hematologic tests can play a role to monitor physiologic processes, such as electrolyte balance, renal function, oxygenation, and blood counts (white blood cell, hemoglobin, and platelets).

In addition, elevation in serum ammonia appears to clinically correlate with hepatic encephalopathy. However, they are not required to make the diagnosis. For a number of reasons, use of ammonia levels as a prognostic or management tool in cases of encephalopathy has been a topic of controversy and should not be used thusly.